The goal of this Project is to identify a subset of first-degree relatives (FDRs) of probands with rheumatoid[unreadable] arthritis (RA) who are currently asymptomatic but who demonstrate both genotypic and phenotypic[unreadable] characteristics that are highly predictive of the development of RA within 3-5 years. We believe that[unreadable] identifying and further characterizing this very high risk population is key to the future goal of developing a[unreadable] primary prevention strategy that would target those individuals for therapeutic intervention prior to the onset[unreadable] of clinically active RA. As part of a funded R01, over the next five years we will finish enrolling and fully[unreadable] evaluating 2100 FDRs of probands with RA. Based on preliminary data, we expect to find a substantial[unreadable] number of FDRs who exhibit patterns of RA-related autoantibodies associated with progression to RA but[unreadable] who do not yet have clinically active disease. From the probands as well as these FDRs, we will also obtain[unreadable] biologic samples that can be used for DNA and other biomarker analysis. We are funded in that R01 to[unreadable] perform RA-related autoantibody and HLA-DR shared epitope analysis, and to re-evaluate FDRs serially in[unreadable] order to follow clinical phenotypes and obtain serial biologic samples. Because of the study design, FDRs[unreadable] can also be readily stratified for the new studies we propose herein by clinical phenotype, RA shared epitope[unreadable] or other genotype, and autoantibody status. Based on additional preliminary data, we expect to find, using[unreadable] both cross sectional and serial analyses, that the RA-associated autoantibody positive FDR group can be[unreadable] further divided into a population that does not exhibit additional biomarkers that are very likely to be[unreadable] associated with progression to clinically active RA, and a population that does exhibit such features of[unreadable] progression. We also expect to find evidence of B and T cell dysfunction in unaffected FDRs who exhibit RArelated[unreadable] autoantibodies and will have a unique opportunity to detect pathogenic T cell epitopes. To[unreadable] accomplish these goals, we propose the following Specific Aims:[unreadable] Specific Aim #1: Determine the proportion of asymptomatic autoantibody-positive FDRs who also exhibit[unreadable] additional biomarkers typically found in patients with active RA.[unreadable] Specific Aim #2: Determine in asymptomatic FDRs the relationships of RA-related autoantibodies and[unreadable] biomarkers to the presence of specific genetic alleles and HLA haplotypes that are associated with the[unreadable] classification of active RA.[unreadable] Specific Aim #3: Examine FDRs who exhibit RA-related autoantibodies for the presence of dysregulated B[unreadable] and T cell immune responses to RA-related autoantigens.[unreadable]